The avermectins (previously referred to as C-076 compounds) are a series of compounds produced by fermentation of avermectin producing strains of Streptomyces avermitilis and derivatives thereof. The morphological characteristics of the culture are completely described in U.S. Pat. No. 4,310,519. The production, isolation, and structure determination of the avermectins are fully described in Albers-Schonberg et al J. Am. Chem. Soc. 1981, 103, 4216-4221 and references cited therein. The conversion of natural avermectin B.sub.1 to 22,23-dihydro-avermectin B.sub.1, the potent broad spectrum anthelmintic agent known as ivermectin, has also been described in the literature (Chabala et al J. Med. Chem. 1980, 23, 1134-1136). The naturally occurring avermectins and the instant derivatives thereof have a very high degree of anthelmintic and anti-parasitic activity.
The naturally occurring avermectins are a series of macrocyclic lactones which are substituted at position 13 with a disaccharide consisting of two oleandrose residues. The natural compounds have the following general structure: ##STR1## wherein the broken line indicates a single or double bond at the 22,23-position and;
R.sub.1 is hydroxy and is present only when said broken line indicates a single bond;
R.sub.2 is iso-propyl or sec-butyl; and
R.sub.3 is methoxy or hydroxy.
There are eight major natural avermectin compounds, designated A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b. These designations are based on the structure of the individual compounds as shown in the following table (referring to the foregoing structural formula).
______________________________________ Compound broken line R.sub.1 R.sub.2 R.sub.3 ______________________________________ A1a 22,23-double bond ---- sec-butyl --OCH.sub.3 A1b 22,23-double bond ---- iso-propyl --OCH.sub.3 A2a 22,23-single bond --OH sec-butyl --OCH.sub.3 A2b 22,23-single bond --OH iso-propyl --OCH.sub.3 B1a 22,23-double bond ---- sec-butyl --OH B1b 22,23-double bond ---- iso-propyl --OH B2a 22,23-single bond --OH sec-butyl --OH B2b 22,23-single bond --OH iso-propyl --OH ______________________________________
The avermectins are generally isolated as mixtures of the a and b components (typically .gtoreq.80% a and .ltoreq.20% b). Such compounds differ only in the nature of the R.sub.2 substitutent and this minor structural difference has been found to have very little effect on the chemical reactivity or biological activity of the compounds. Thus although the a and b components can be separated from each other by chromatography this is not necessary and hence is not normally done. The presence of a mixture of a and b components is indicated by dropping the a or b from the designation of the compound. A mixture of avermectin B1a and avermectin B1b is thus referred to as avermectin B1.
A related family of natural products is known as the milbemycins. The milbemycins have the same basic structure as the avermectins but have no substitution at position 13 and have a methyl or ethyl group at position 25 (R.sub.2 =methyl or ethyl rather than isopropyl or sec-butyl as in the avermectins). The milbemycins and the fermentation conditions used to prepare them are described in U.S. Pat. No. 3,950,360. Closely related 13-deoxy-avermectin aglycones are prepared by chemical modification of the natural avermectins and have been described in U.S. Pat. Nos. 4,171,134 and 4,173,571. Avermectin aglycones, which may also be used as starting material for the instant compounds are disclosed in U.S. Pat. No. 4,206,205. U.S. Pat. No. 4,457,920 described 4a-derivatives of avermectin compounds in which the 4a-substitutents are hydroxy, acetyloxy, benzoyloxy, pyridinyl carbonyloxy, pyrrolyl carbonyloxy or carboxyethanoyloxy. This reference also discloses the preparation of the 4a-hydroxy compounds which are the starting materials for the instant compounds.
Japanese patent publication 02,017,191 also describes compounds with 4a-substituents. The 4a-substitutents disclosed include azido, halo, cyano, alkanoyloxy, alkoxy, and nitrogen and sulfur substituted derivatives.
Recently a number of related compounds have been described in European Patent Application EPO 170,006 and U.K. aplication 2,166,436 (see also Carter et al., J. Antibiotics 1988, 41, 519-529). These compounds are essentially 13-deoxy-avermectin aglycones in which the R.sub.2 side chain contains a double bond and, in some cases, includes additional carbon atoms.
Chemically modified derivatives of this group of compounds have recently become known. In particular compounds containing a N-methoxyimino substituent attached to the C-23 position are described in UK Patent Application GB 2 192 630 A and European Patent Application 0 237 341 A1. Moxidectin is the generic name for a compound of this group with the chemical name [6R, 25S(E)]-5-0-demethyl-28-deoxy-25-(1,3-dimethyl-1-butenyl)-6,28-epoxy-23-(m ethoximino) Milbemycin B.
Recent publications have described the synthesis of avermectin A1a (Danishefsky et al, J. Am. Chem. Soc. 1989, 111, 2967) and avermectin B1a (Hanessian et al, J. Am. Chem. Soc. 1986, 108, 2776). Research on deconjugation and epimerization of avermectin C-2 stereoisomers is described in the two synthetic publications cited above as well as in Hanessian et al (J. Am. Chem. Soc. 1987, 109, 7063) and Fraser-Reid et al (J. Am. Chem. Soc. 1987, 109, 933).
The avermectins are highly potent anthelminthic and antiparasitic agents and are relatively non-toxic to most mammalian species. However, the avermectins are highly toxic to certain mammalian species and this fact precludes the use of avermectins for some applications. In addition, the avermectins are ineffective against some parasites and resistant strains of previously susceptible parasites may evolve. Thus it is desirable to discover novel avermectin analogs with improved activity and/or lower mammalian toxicity.